(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoylaminomethyl-1-pyrr olidin-3-yl]thio-1-methyl-1-carba-2-penem-3-carboxylic acid represented by the following formula (hereinafter referred to as S-4661 in the specification) is a pyrrolidylthiocarbapenem derivative. S-4661 is a useful compound as an antimicrobial drug, and orally or parenterally administered. ##STR2##
S-4661 itself is described in Japanese Laid-Open Patent Publication (Kokai) No. 5-294970. However, no crystal of S-4661 is described in the Publication. When S-4661 is produced, conventionally, a process for producing it in an amorphous form only is known. However, an amorphous solid of S-4661 has insufficient stability during storage. Therefore, when S-4661 is stored under ordinary storage conditions for a long period, the color thereof is changed, and the purity disadvantageously deteriorates. Thus, it is desired to prepare a crystalline preparation of S-4661 having a higher storage stability than an amorphous preparation. In particular, among the crystalline preparations, a preparation containing an inner salt is more preferable in that it is unnecessary to use an additive in a large amount in order to form a salt.
Furthermore, among the crystalline preparations of S-4661, a crystalline lyophilized preparation is preferable, because it is generally easy to ensure sterility of a lyophilized preparation and to remove particulate matters from the lyophilized preparation.
As a general process for producing a lyophilized preparation, a variety of processes are conventionally known. For example, Japanese Laid-Open Patent Publication (Kokai) Nos. 61-172878, 63-174927 and 4-59730 disclose that NaCl is added to a solution before lyophilization in order to improve solubility and stability of an amorphous lyophilized preparation. Japanese Laid-Open Patent Publication (Kokai) No. 4-338332 discloses that Na.sub.2 CO.sub.3 or NaHCO.sub.3 is added to a drug in a form of a hydrochloride salt so that an insoluble free base is not deposited.
The following processes are known as a process for obtaining a crystalline lyophilized preparation: for example, Japanese Patent Publication (Kokoku) No. 4-66202 discloses that an aqueous solution of a drug is allowed to be in a supercooled state without freezing, and crystal nuclei are generated in the supercooled state; Japanese Patent Publication (Kokoku) No. 60-19758 discloses that an aqueous solution of a drug containing 2 to 25 v/v % of alcohol is gradually cooled to freeze water and crystal nuclei are generated in a state of a concentrated alcohol solution; and Japanese Patent Publication (Kokoku) Nos. 60-19759, 03-74643 and Japanese Laid-Open Patent Publication (Kokai) No. 5-271241 disclose that an aqueous solution of a drug is frozen at a predetermined temperature, then warmed to a predetermined temperature, and retained at a constant temperature.
Conditions suitable for lyophilization are varied depending on the drugs to be lyophilized. Therefore, the aforementioned known processes are not necessarily suitable for a process for producing a lyophilized preparation containing the crystal of S-4661. For example, since the process for lyophilization by freezing an aqueous solution containing S-4661 at a predetermined temperature and retaining it at a constant temperature takes a very long time, it is not suitable as an industrial process.
As described above, no process suitable to obtain a crystal of S-4661, in particular, an inner salt crystal, and no lyophilization process suitable to obtain a lyophilized preparation containing the crystal have been found yet.